Jaw-Tumor Hyperparathyroidism Syndrome as Reproductive Disease Model

一名来自HPT-JT家族的26岁初产妇因终身月经过多导致贫血而被转诊。 已知她的家族成员在CDC 73/HRPT 2中携带L95 P错义突变，并且有几个人受到HPT-JT的影响。 患者希望治疗月经过多并能够怀孕。 对患者进行基因分型，发现其为杂合子的生殖系L95 P parafibromin错义突变。 体格检查可见宫颈外口大外翻。经阴道超声和磁共振成像显示子宫内膜增大，结合区增厚。 手术宫腔镜检查显示子宫腔充满了不典型的，纤维性子宫内膜息肉样结构，从底部延伸到子宫颈。 手术切除息肉与电灼和多个粘液填充囊肿看到。这些息肉样结构的组织学检查显示良性子宫腺肌瘤。 在手术室将一个新的黄体酮IUD放置在宫腔内以治疗月经过多。 5个月后，患者出现持续性月经过多。 然后对她先前手术的组织学组织样本进行芳香化酶染色。 这种染色显示，与没有腺肌瘤的正常对照相比，她的腺肌瘤内芳香化酶过表达。 患者开始接受芳香酶抑制剂治疗。 在芳香化酶抑制剂开始后6个月随访时，患者注意到子宫出血减少，她的子宫内膜内膜薄至4 mm。 术后，患者接受了芳香酶抑制剂和孕酮宫内节育器的药物治疗。这种治疗持续了总共10个月，导致她的症状持续改善。患者希望怀孕，随访宫腔镜检查记录了子宫腔的显著改善，有几个较小的息肉，其中最大的为3 mm。 IUD和剩余的小息肉被手术切除。 手术后3个月停止使用芳香酶抑制剂，患者在下一个排卵周期自发妊娠。 她有一个简单的怀孕，导致一个4479克女性足月自然阴道分娩。 影像学显示子宫内膜衬里增大，结合带增厚。在手术宫腔镜下，多个不典型的子宫内膜息肉样病变充满整个子宫腔，并被切除。 组织学检查证实病变为芳香化酶表达丰富的腺肌瘤。 术后治疗包括芳香酶抑制剂。 患者的月经过多，这是以前对孕酮宫内节育器治疗，解决与芳香酶抑制剂。治疗10个月后，芳香化酶抑制剂停药，再次宫腔镜检查显示宫腔明显改善。 患者随后在第一个自然周期怀孕，并分娩了一名健康的足月婴儿。 据我们所知，芳香化酶表达的评估子宫病理HPT-JT尚未报道。 作为该项目的一部分，芳香化酶抑制剂的使用导致了显著的临床改善，减少月经过多和怀孕的能力。 这可能代表了一种新的治疗方法的药物治疗良性子宫病变的妇女HPT-JT。 除了为这种疾病开发新的临床治疗方法外，我们还利用这种罕见的疾病在实验室中研究妇科疾病。 目前，正在努力创造新的体外细胞系来研究这种疾病。 这些细胞系可能成为用于研究良性子宫内膜疾病以及非典型子宫恶性肿瘤的重要系统，其中缺乏用于体外研究的细胞系。

A 26 year old nulligravida woman from a family with HPT-JT was referred for life-long menorrhagia resulting in anemia. Members of her family were known to carry a L95P missense mutation in CDC73/HRPT2, and several were affected with HPT-JT. The patient desired management of her menorrhagia and the ability to conceive. The patient was genotyped and found to be heterozygous for a germline L95P parafibromin missense mutation. Physical examination was notable for a large everted external cervical os. Transvaginal ultrasound and magnetic resonance imaging demonstrated an enlarged endometrial lining with thickening of the junctional zone. Operative hysteroscopy revealed a uterine cavity filled with atypical, fibrous endometrial polyp-like structures which extended from the fundus and down through the cervix. The polyps were surgically removed with electrocautery and multiple mucous filled cysts were seen. Histologic examination of these polypoid structures revealed benign uterine adenomyomas. A new progesterone IUD was placed in the uterine cavity in the operating room for management of menorrhagia. Five months later the patient presented with persistence of menorrhagia. Staining for aromatase was then performed on her histologic tissue samples from the prior surgery. This staining revealed an over-expression of aromatase within her adenomyomas as compared to normal controls without adenomyomas. The patient was started on an aromatase inhibitor. Upon follow up six months after the aromatase inhibitor was started, the patient noted decreased uterine bleeding and her endometrial lining was thin at 4mm. Post-operatively, the patient received medical therapy with an aromatase inhibitor and a progesterone intrauterine device. This treatment was continued for a total of ten months resulting in continued improvement in her symptoms. The patient desired pregnancy and a follow-up hysteroscopy documented dramatic improvement in the uterine cavity with a few smaller polyps the largest of which was 3mm. The IUD and the remaining small polyps were surgically removed. The aromatase inhibitor was discontinued three months after surgery and the patient became spontaneously pregnant with her next ovulatory cycle. She had an uncomplicated pregnancy resulting in a term spontaneous vaginal delivery of a 4479gm female. Imaging demonstrated an enlarged endometrial lining and thickening of the junctional zone. At operative hysteroscopy, multiple atypical endometrial polyp-like lesions filled the entire uterine cavity and were removed. Histologic evaluation demonstrated the lesions to be adenomyomas with an abundance of aromatase expression. Postoperative treatment included an aromatase inhibitor. The patients menorrhagia, which had previously been resistant to progesterone IUD therapy, resolved with the aromatase inhibitor. After ten months of this treatment, the aromatase inhibitor was discontinued and a repeat hysteroscopy revealed a markedly improved uterine cavity. The patient subsequently became pregnant on her first natural cycle and delivered a healthy term infant. To our knowledge, assessment of aromatase expression in the uterine pathology of HPT-JT has not been reported. As part of this project, the use of aromatase inhibitors resulted in marked clinical improvement, decreased menorrhagia, and the ability to conceive. This may represent a novel therapy for the medical therapy of benign uterine lesions in women with HPT-JT. In addition to developing novel clinical therapies for this disorder, we have utilized this rare condition to study gynecologic conditions in the laboratory. Currently, efforts are underway to create novel in vitro cell lines to study this disorder. These cell lines could become important systems used to study benign endometrial diseases, as well as atypical uterine malignancies, where cells lines for in vitro study are lacking.